Distributed neurodegenerative changes 2-28 days after ventral hippocampal excitotoxic lesions in rats

An enhanced sensitivity to the behavioral effects of dopamine (DA) agonists in adult rats occurs after cytotoxic lesions of the ventral hippocampus (vHPC). While some of these behavioral changes may model specific abnormalities in schizophrenia patients, little is known about the cellular events that underlie vHPC lesion-induced behavioral DA 'supersensitivity'. Neuropathological consequences of excitotoxin lesions of the vHPC were investigated in this study. Adult male rats received vehicle or ibotenic acid infusions into the vHPC, using parameters that produce an enhanced sensitivity to the prepulse inhibition-disruptive effects of the DA agonist apomorphine, 1 month post-lesion. A total of 27 rats were sacrificed, 2, 7, 14, 21 or 28 days post-lesion. Amino-cupric-silver staining demonstrated degenerative changes throughout the hippocampus, and in hippocampal efferent projections to forebrain structures, including the septal nucleus and nucleus accumbens (NAC), and within the olfactory tubercle (OT) and orbital cortex. Silver-impregnated fibers were identified in the substantia nigra reticulata (SNr), NAC, OT, septum and orbital cortex. Some degenerative changes were noted at the earliest time point (2 days post-lesion), while others were delayed in appearance. Adjacent sections stained for tyrosine hydroxylase (TH) immunocytochemistry revealed reduced TH labeling through forebrain DA terminal fields 28 days, but not 14 days after VH lesions. Excitotoxic lesions of the vHPC result in distributed neurotoxic changes in subcortical and cortical brain regions; these changes may contribute to the delayed emergence of DA-mediated behavioral abnormalities in these animals.